Pharmacokinetic and pharmacodynamic evaluation of a nanotechnological topical formulation of lidocaine/prilocaine (nanorap) in healthy volunteers.

BACKGROUND: Nanorap is a new nanotechnological formulation for topical anesthesia composed of lidocaine (2.5%) and prilocaine (2.5%). This study evaluated the pharmacokinetics of Nanorap. For the determination of lidocaine and prilocaine in human plasma, a new method using high-performance liquid chromatography coupled with tandem mass spectrometry was developed. Nanorap pharmacodynamic (PD) and its physical proprieties were also evaluated. METHODS: Nanorap was administered by topical application of 2 g to healthy volunteers, and blood samples were collected for the pharmacokinetics analysis. The drugs were extracted from plasma by liquid-liquid extraction with ether/hexane (80/20, vol/vol). The chromatography separation was performed on a Genesis C18 analytical column 4 µm (100 × 2.1 mm i.d.) with a mobile phase of methanol/acetonitrile/water (40/30/30, for lidocaine, and 50/30/20, for prilocaine, vol/vol/vol) + 2 mM of ammonium acetate and ropivacaine as internal standard. The drugs were quantified using a mass spectrometer with an electrospray source in the electrospray ionization positive mode configured for multiple reaction monitoring. The PD of Nanorap was evaluated with the use of a visual analog scale. Nanorap was characterized by cryofracture. RESULTS: The chromatography run-time was 5.5 minutes for lidocaine and 3.3 minutes for prilocaine, and the lower limit of quantification was 0.05 ng/mL for both drugs. Mean Cmax was 6.62 and 1.72 ng/mL for lidocaine and prilocaine, respectively. Median Tmax was 6.5 hours for both drugs. Nanocapsules had a mean size of 88 nm and mean drug association of 92.5% and 89% for lidocaine and prilocaine, respectively. The PD study showed that Nanorap has a sufficient analgesic effect (>30% reduction in pain) after 10 minutes of application. CONCLUSIONS: A new simple, selective, and sensitive method for determination of lidocaine and prilocaine in human plasma was developed. Nanorap generated safe plasma levels of the drugs and satisfactory analgesic effect.

Evaluation and application of a high performance liquid chromatographic method for prilocaine analysis in human plasma.

BACKGROUND: Prilocaine, a local anesthetic of the amide type, is frequently applied in substantial doses during tumescent liposuction. Although it cannot be excluded that the subcutaneously infiltrated narcotic may enter the circulation and trigger adverse systemic reactions, prilocaine plasma levels have rarely been measured during routine tumescent surgery. We established and evaluated a high performance liquid chromatography (HPLC) method for analysis of this narcotic and used it to measure the drug in plasma samples drawn in the course of tumescent liposuction with prilocaine local anesthesia. METHODS: After approval by the local ethics committee and written informed consent, 283 heparin plasma samples were collected from 132 patients during and about 6, 12, and 24 hours after tumescent liposuction with prilocaine infused at doses of 19 +/- 5 mg/kg body weight. Calibrators and controls were prepared by spiking blank plasma with prilocaine. Following addition of internal standard and sodium hydroxide, plasma was extracted with diisopropyl ether. For HPLC analysis, dried extracts were dissolved in methanol - 4.35 mmol/L ammonium phosphate, pH7.0, (60:40 v/v) and applied to a Synergy 4 microm Fusion-RP column (250 x 4.6 mm) rinsed with the same buffer. Analytes were detected by absorption at 237 nm. For liquid chromatography mass spectrometry (LC-MS), extracts were dissolved in acetonitrile - 2 mmol/L ammonium acetate - formic acid (5:95:0.2 v/v/v), applied to a Synergy 4 microm Polar-RP column (75 x 2 mm), and eluted with a gradient of acetonitrile in 2 mmol/L ammonium acetate - formic acid. Analytes were detected by an ion trap mass spectrometer with electrospray ionization run in a MS/MS mode. RESULTS: In the HPLC assay established, prilocaine and the internal standard lidocaine eluted at about 14 and 25 minutes, respectively. The limit of detection of prilocaine was 0.002 mg/L, the measurable range extended to 30 mg/L. At prilocaine concentrations between 0.08 and 10.0 mg/L, inter-assay coefficients of variation of 6.2 to 9.9% were obtained. Analyses of plasma pools spiked with variable amounts of prilocaine showed recoveries of 91-101%. Results measured in 20 plasma samples by both HPLC and an independent LC-MS assay agreed acceptably (Y(HPLC) = 0.07 + 1.19x(LC-MS), R 0.98). Prilocaine plasma concentrations measured by HPLC in 132 plasma samples drawn in the late phase of liposuction ranged between 0.01 and 32.0 mg/L, roughly one third of all samples exhibiting levels above 5 mg/L. About 6 hours later, prilocaine levels measured in 46 plasma samples were lower (0.13 - 1.56 mg/L) and decreased further in the evening of the operative day (n = 49, 0.10 - 0.62 mg/L) and on the morning of the first postoperative day (n = 55, 0.03 - 0.25 mg/L). CONCLUSIONS: An HPLC method for determination of prilocaine was established and successfully applied to analysis of this drug in human plasma. Our results clearly indicate that during tumescent liposuction a significant portion of the subcutaneously infiltrated prilocaine enters the circulation, resulting in potentially harmful blood levels in about one third of the patients studied. 6 hours after liposuction, however, all samples exhibited prilocaine plasma levels far below a critical concentration and these levels further decreased in the evening of the day of treatment and on the next morning.

A pharmacokinetic study of a topical anesthetic (EMLA® ) in mouse soft tissue laceration.

The use of topical anesthesia instead of injection of local anesthetics for managing soft tissue lacerations in the emergency situations may be a relief for both patients and surgeons. Topical anesthesia in the form of a cream eutectic mixture of local anesthetics (EMLA®) containing 2.5% lidocaine and 2.5% prilocaine has been reported as an efficient anesthetic on skin before venipuncture anesthesia and as an alternative to injection anesthesia in some minor surgery situations. The aim of this study was to compare the pharmacokinetics of EMLA® when applied in a laceration with topical skin application in the mouse. A total of 120 Albino Laboratory-bred strain mouse (BALB-c) male mice were divided into three groups with regard to application mode of EMLA®. Group A: with laceration, 48 mice; Group B: on intact shaved skin, 48 mice; Group C: control group (24 mice) with same procedures but without application of EMLA®. Blood levels were collected at 0, 10, 20, 30, 45, 60, 75, and 90 min post-EMLA® application. Plasma sample analysis was carried out by employing liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method, and the pharmacokinetic analysis of the mouse plasma samples was estimated by standard non-compartmental methods. The pharmacokinetic parameters of lidocaine and prilocaine were significantly altered following EMLA® application to lacerated mouse skin in contrast to intact skin. The absorption of lidocaine and prilocaine was rapid following application of EMLA® to lacerated and intact mouse skin. Maximum drug plasma concentration (C(max) ) and area under the drug plasma concentration-time curve (AUC) values of lidocaine were significantly increased by 448.6% and 161.5%, respectively, following application of EMLA to lacerated mouse skin in comparison with intact mouse skin. Similarly, prilocaine's C(max) and AUC values were also increased by 384% and 265.7%, respectively, following EMLA application to lacerated mouse skin, in contrast to intact skin. Further pharmacokinetic studies on different carriers of lidocaine/prilocaine are warranted before any firm conclusions for the clinic can be drawn.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

BACKGROUND AND OBJECTIVE: Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. METHODS: This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. RESULTS: A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 µg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. CONCLUSIONS: This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.

Polyacrylonitrile / graphene oxide nanofibers for packed sorbent microextraction of drugs and their metabolites from human plasma samples.

In the present study, a new graphene based nanofibers material (Polyacrylonitrile/Graphene Oxide (PAN/GO)) was used for microextraction by packed sorbent (MEPS). The PAN/GO nanofiber was synthesized using the electrospinning technique. MEPS online with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for the extraction and determination of two local anesthetic drugs (lidocaine, prilocaine) and their major metabolites (2,6-xylidine, o-toluidine) in human plasma samples. Parameters affecting the extraction efficiency were investigated and optimized (including sample pH, washing solution and elution solution). The validation of the method was based on FDA (Food and Drug Administration) guidelines for bioanalytical methods. The calibration curve ranged from 2.00 to 2000 nmol/L for lidocaine and prilocaine, and from 10.0 to 2000 nmol/L for 2,6-xylidine and o-toluidine. The coefficient of determination (R2) values were 0.996, 0.995, 0.995, 0.996 (n = 3) for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The extraction recovery was 93.0% for lidocaine, 96.0% for prilocaine, 68.0% for 2,6-xylidine and 69.0% for o-toluidine. The limits of detection (LODs) were 0.25, 0.50, 2.50, 1.25 nmol/L for lidocaine, prilocaine, 2,6-xylidine and o-toluidine, respectively. The lower limits of quantification (LLOQs) were 2.0 nmol/L for lidocaine and prilocaine, and 10 nmol/L for 2,6-xylidine and o-toluidine, respectively. The accuracy values for the quality control (QC) samples were in the range of 91.0-111% for lidocaine, 92.0-118% for prilocaine, 84.0-98.0% for 2,6-xylidine and 82.0-90.0% for o-toluidine. The inter-day precisions for QC samples ranged from 7.0% to 11.8% for lidocaine, from 8.6% to 11.7% for prilocaine, from 8.0% to 10.0% for 2,6-xylidine and from 8.0% to 9.0% for o-toluidine. The matrix effect values were in the range of -2.3% to -8.6% for lidocaine, -2.7% to -10.2% for prilocaine, 4.8%-5.2% for 2, 6-xylidine and -8.2% to 9.4% for o-toluidine.

Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection.

A 91-yr-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery of bursitis of the olecranon. Twenty minutes after infraclavicular injection of 30 mL of mepivacaine 1% (Scandicain) and 5 min after supplementation of 10 mL of prilocaine 1% (Xylonest) using an axillary approach, the patient complained of agitation and dizziness and became unresponsive to verbal commands. In addition, supraventricular extrasystole with bigeminy occurred. Local anesthetic toxicity was suspected and a dose of 200 mL of a 20% lipid emulsion was infused. Symptoms of central nervous system and cardiac toxicity disappeared within 5 and 15 min after the first lipid injection, respectively. Plasma concentrations of local anesthetics were determined before, 20, and 40 min after lipid infusion and were 4.08, 2.30, and 1.73 microg/mL for mepivacaine and 0.92, 0.35, and 0.24 microg/mL for prilocaine. These concentrations are below previously reported thresholds of toxicity above 5 microg/mL for both local anesthetics. Signs of toxicity resolved and the patient underwent the scheduled surgical procedure uneventfully under brachial plexus blockade.

The "inverted cup" -- a novel in vitro release technique for drugs in lipid formulations.

The aim of this study was to develop a membrane-free in vitro release method for drugs in lipid formulations. It was intended to be applicable to as wide a range as possible of preparations, independently of their polarity and viscosity. The principle of the novel technique is to keep the sample suspended in the release medium in an inverted glass cup, allowing a possible phase transition or swelling. Thirteen formulations containing bupivacaine, lidocaine and/or prilocaine in lipid vehicles with different physical properties were prepared and examined. When possible, in vitro release profiles obtained by the new method were compared to profiles obtained by earlier techniques. For three formulations of either bupivacaine or lidocaine in polar lipid formulations, in vitro release profiles were evaluated in relation to in vivo data, from nerve block and pharmacokinetic studies in rats. Preparations that could be investigated both by the "inverted cup" and by the earlier published "single drop" technique generally showed good agreement between the two release profiles. In the case of the polar lipid formulations, arterial blood concentration curves in rats could reasonably be predicted from the in vitro release profiles. In conclusion, the "inverted cup" technique should potentially be applicable to a wide range of lipid formulations of drugs, both for physico-chemical characterisation and for obtaining in vitro -- in vivo correlations.

Simultaneous determination of bupivacaine, mepivacain, prilocaine and ropivacain in human serum by liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometric (LC-MS-MS) method with a rapid and simple sample preparation was developed and validated for the simultaneous determination of the local anesthetics bupivacaine, mepivacaine, prilocaine and ropivacaine in human serum. An external calibration was used. The mass spectrometer was operated in the multiple reaction monitoring mode. A good quadratic response over the range of 1.0-200.0 ng/ml was demonstrated. The accuracy for bupivacaine ranged from 93.2 to 105.7%, for mepivacaine from 96.2 to 104.3%, for prilocaine from 94.6 to 105.7% and for ropivacaine from 94.3 to 104.0%, respectively. The limit of quantification was 1.0 ng/ml for all substances. This method is suitable for pharmacokinetic studies.

Temporal variations in transcutaneous passage of drugs: the example of lidocaine in children and in rats.

Because a eutectic mixture of lidocaine and procaine (EMLA cream) is used to treat pain in children who are undergoing venipuncture for screening clinical presurgery laboratory tests, this study was designed to investigate the influence of the time of application of EMLA cream on lidocaine transcutaneous absorption in children. The same phenomenon was also studied in rats. Local application of EMLA (right and left cubital fossae) was performed 1 hour before venipuncture in two groups of children (0.5 g/kg body weight at two sites), at 08:15 or 16.15 h; blood samples were performed 1 h later. Two groups of five rats each received 12 mg/kg lidocaine at 07:30 or 19.30 h by application to the back skin. Blood samples were collected 0.5, 1, 1.5, 2, 3, and 4 h after application. Plasma lidocaine levels were assayed according to an immunoenzymatic method (Abbott). Our data indicate that the lidocaine plasma levels were significantly different: higher in the evening for the children or in the morning for the rats. The plasma level of the local anesthetics (LA) represents an elimination route and thus may be inversely correlated to the skin amount of the LA.

A microdialysis model to examine nasal drug delivery and olfactory absorption in rats using lidocaine hydrochloride as a model drug.

Targeting of the central nervous system by direct drug transport from the nose to the brain has gained increased attention through the last decade. In the present study, a model for olfactory drug absorption has been investigated using intravenous and unilateral nasal administration of lidocaine hydrochloride in rats. To investigate the possible drug delivery aspects of this route of transport to a central part of the brain a microdialysis model using in vivo recovery by calibrator was applied to the systemic blood and to right and left striatum. The integrity of the blood-brain barrier was evaluated following microdialysis probe implantation. The in vivo experiments were carried out as a cross-over study in rats. The drainage from the nasal cavity was not restricted by occlusion. It was found that true unbound lidocaine concentrations could be calculated from in vivo recovery measurements of retrodialysis of prilocaine hydrochloride. The relative in vivo recoveries in striatum (11.3%) and blood (24.0%) were significantly lower than in vitro (31.3 and 44.9%). The blood-brain barrier was found to retain its physical integrity when evaluated one hour after probe implantation. From pharmacokinetic modelling of the time-concentration curves it was found that the absorption rates and area under the curve (AUC) values of lidocaine in left and right striatum were not statistically different following nasal and intravenous administration, respectively. The average nasal bioavailabilities of lidocaine in blood, left and right striatum were 85, 103 and 129%, respectively. It was concluded that no significant olfactory absorption to striatum was evident in the present study. However, the method should be applicable to studies of drug delivery to blood and brain following nasal administration of other drugs.

Tetracaine versus lidocaine-prilocaine for preventing venipuncture-induced pain in children.

The efficacy of tetracaine cream versus that of lidocaine-prilocaine cream for the prevention of pain in children undergoing venipuncture was studied. Hospital inpatients 1-15 years of age received, on the back of each hand, a 30-minute application of tetracaine 4% cream or a 60-minute application of lidocaine-prilocaine cream (EMLA, Astra) before undergoing scheduled venipuncture. The phlebotomists in this open, randomized trial evaluated the efficacy of the cream at the moment of venipuncture as adequate, inadequate, or inconclusive. Blood samples were taken immediately after venipuncture from 10 patients one to five years of age to measure the serum concentrations of tetracaine and its metabolite, N-butyl-p-aminobenzoic acid. Lidocaine-prilocaine cream was significantly more efficacious in preventing pain than tetracaine 4% cream (97% of the former group [n = 32] had adequate pain relief, compared with 76% of the latter [n = 34]. The only adverse effects observed were mild local erythema in the tetracaine group and local skin blanching in the lidocaine-prilocaine group. No tetracaine could be detected in serum, and the serum concentrations of N-butyl-p-aminobenzoic acid ranged from 0 to 1.8 mg/l. Statistically, lidocaine-prilocaine cream was more efficacious than tetracaine 4% cream, but the difference is of minor clinical significance and is outweighed by the practical advantages of tetracaine 4% cream, namely the shorter application time, vasodilation and lower cost.

Stereoselective determination of R(-)- and S(+)-prilocaine in human serum using a brush-type chiral stationary phase, solid-phase extraction and UV detection.

A chiral HPLC method was developed for the quantitation of R(-)- and S(+)-prilocaine in human serum. The method involves sensitive and selective detection of R(-)- and S(+)-prilocaine using normal-phase chiral HPLC on a pirkle-type naphthyl ethylamine stationary phase (Sumichiral OA-4700, 250 mm x 4 mm i.d.) at ambient temperature with a flow rate of 0.8 ml min-1. A sample clean-up procedure was used for isolation of the analytes of interest from human serum using Bond-Elut C18 columns with high recovery and selectivity. The detection limits were 4 ng ml-1 for R-prilocaine and 5 ng ml-1 for S-prilocaine. The limits of quantitation were 10 ng ml-1 for both enantiomers. Linear calibration curves in the 10-1000 ng ml-1 range showed good coefficients of determination > 0.999 (n = 3). Precision and accuracy of the method were within 4-5.8% and 1.5-4.8% respectively for R(-)-prilocaine, and 2.8-5.7% and 3.2-5.2% respectively for S(+)-prilocaine.

Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study.

The purpose of this study was to determine the safety and pharmacokinetics of a eutectic mixture of local anesthetics (EMLA) used to ameliorate postburn pruritus after application onto newly formed, intact skin in children. EMLA was applied once to an itchy site where healed skin had formed. Serial blood samples were collected to measure lidocaine, prilocaine, o-toluidine, and methemoglobin. Maximal plasma concentration, minimal plasma concentration, time to achieve the maximal plasma concentration, elimination half-life, and area under the concentration-time curve were calculated. Vital signs, oxygen saturation, clinical signs of hypoxia, and itch intensity were measured. Five children had 15.7 +/- 2.54 g (+/- SD) of EMLA applied to a skin surface area of 93.0 +/- 37.0 cm2. Lidocaine and prilocaine concentrations were below toxic levels; o-toluidine was not detected. Methemoglobin remained between 1 and 3%; patients did not exhibit any clinical signs of hypoxia. Mean oxygen saturation was 98.9 +/- 0.01%. The mean number of pruritic episodes and antihistamine breakthrough doses were greater in the 2 prestudy control days compared with study day 3 (P = 0.01 and P = 0.03, respectively). Skin at the site of EMLA application remained anesthetized for 12 to 13 hours. In this small pilot study, EMLA seems to be a safe, novel treatment for postburn pruritus in burned children when applied to newly healed, intact skin.

Are intraligamentary injections intravascular?

A pressure type syringe was used to give intraligamentary injections (IL) to upper teeth of two formulations commonly used in general practice, lignocaine and prilocaine. Assay of plasma levels of drug was carried out by high performance liquid chromatography. Results of assays after intraligamentary injections were then compared with results of assays after intravenous injections of plain drug in the same subjects. Both formulations of local anaesthetic were found as peak levels in the circulation, presumably after intraosseous spread, by 2 minutes following the intraligamentary injections. For lignocaine the peak amount was nearly 7% of the intravenous dose and for prilocaine the peak amount was 25% of the intravenous dose, at 2 minutes after injection. It was concluded that IL injections for healthy adults were unlikely to cause systemic unwanted effects when given in small doses.

Topical anaesthesia of gingival mucosa by 5% eutectic mixture of lignocaine and prilocaine or by 10% lignocaine spray.

The analgesic effect of topical application of local anaesthetics on the gingival mucosa and the absorption of the local anaesthetics into the blood were investigated in healthy volunteers by using a 5% eutectic mixture of the local anaesthetics lignocaine (100 mg) and prilocaine (100 mg) plus emulsifier (EMLA) or 10% lignocaine (200 mg) spray (Xylocain). The pain threshold on labial gingiva was measured by using the stimulator of an EMG-apparatus and a pair of stimulating electrodes, specially constructed for this purpose. There were no differences between the two methods in producing analgesia which was at its maximum in 13 to 14 minutes, on average. Sensation of the gingiva (pain thresholds), had usually returned to normal within 30 minutes. In the dosages used, the absorption of the local anaesthetics was more rapid after the mixture application than after spray application. No toxic reactions occurred.

Topical application of 5% eutectic mixture of lignocaine and prilocaine (EMLA) before removal of arch bars.

The analgesic effect of topical application of a 5% eutectic mixture of lignocaine and prilocaine (EMLA) was studied in 45 patients undergoing removal of oral arch bars used for the treatment of mandibular fractures. Employing a double-blind technique, either 4 g of the eutectic mixture (EMLA group, n = 15) or 4 g of a similar emulsion containing no local anaesthetic (placebo group, n = 15) was applied to the gingivae using a toothbrush and a standardised technique. In the control group (n = 15), infiltration anaesthesia with lignocaine was used only if requested by the patient during the removal of the arch bars. The patients in the EMLA group had significantly better analgesia (P less than 0.005) of the gingivae just before removal of the arch bars than patients in the placebo group, but by the end of the procedure the difference in analgesia was not significant. The number of patients who found the procedure pain-free was significantly higher in the EMLA group (7/14) than in the placebo group (2/15) (P less than 0.005). The plasma concentrations of both lignocaine and prilocaine were well below the toxic levels. Topical application of EMLA can be recommended for short procedures as an alternative to infiltration.

Knee arthroscopy with local anesthesia in ambulatory patients. Methods, results and patient compliance.

Knee arthroscopy in locally anesthetized ambulatory patients has been performed by filling the knee joint with 50 ml to 60 ml of 0.5% prilocaine, with adrenaline and with additional local infiltration at the sites of puncture. During the arthroscopic procedure the joint cavity is further distended with a mixture of the same local anesthetic diluted 1:10 with physiological saline or Ringer's acetate. During a normal arthroscopy of the knee joint about 500 mg of the local anesthetic is used. In 17 patients the blood concentrations of the local anesthetic used was measured 2.5 min to 135 min after instillation. The highest plasma levels found (after 60 min to 120 min) were still 10 to 15 times lower than an acceptable upper plasma level. These low blood levels probably depend on a slow absorption and that a considerable amount of the local anesthetic is washed out after the arthroscopy. A questionnaire was sent to 278 patients who during a two year period had undergone arthroscopy as an outpatient procedure. The degree of satisfaction for the anesthetic procedure was highest for general anesthesia where 97% were completely satisfied. Sixty-four percent were satisfied when given spinal anesthesia. However, 11% had to be put to sleep due to insufficient spinal block and 12% had headaches more than one day after outpatient spinal anesthesia. Seventy-seven percent were satisfied with local anesthesia. There was no statistical difference between the degree of satisfaction after local or spinal anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of percutaneous anesthesia in cardiac pacemaker implantation]. / Emploi de l'anesthésie transcutanée dans les procédures d'implantation de stimulation cardiaque.

OBJECTIVES: Assess the efficacy of an anesthesic cream for pacemaker implantations. METHODS: Percutaneous anesthesia was studied in a series of permanent pacemaker transvenous implantations. The anesthesic cream composed of a mixture of lidocaine and prilocaine was applied precisely over operative areas after marking the skin. Percutaneous anesthesia should be applied 2 hours before entering the operating room. RESULTS: This percutaneous local anesthesia was perfectly effective for simple replacement procedures. At first implantations, it was used alone in 4 out of 10 cases while intradermal injections were needed to anesthetize the deep layers in the other patients. Serum concentrations indicate very low levels which are tolerated very well. CONCLUSION: Alone or combined with lidocaine infiltration, the use of an anesthesic cream is safe and effective in transvenous pacemaker surgery.

Pharmacokinetics of EMLA cream 5% application to oral mucosa.

Plasma concentrations of lidocaine and prilocaine were measured following the application of a 5% eutectic mixture of local anesthetics (EMLA) topical anesthetic cream to the oral mucosa of twelve subjects. For each subject, a total of 8 g of EMLA was occluded to 18 cm2 of buccal mucosa for 30 min. Analysis was carried out by high-pressure liquid chromatography, and results showed peak concentrations at 40 min for lidocaine and prilocaine. The maximum concentration measured in any subject was 418 ng/ml for lidocaine and 223 ng/ml for prilocaine, well below known toxic levels. No adverse local effects were observed from a 30-min application of EMLA. A follow-up pilot study assessing the clinical efficacy of EMLA for achieving sufficient analgesia for restorative procedures showed that the cream was successful in 75% of subjects tested.